Results of a defined surgical protocol for treating pediatric neurogenic bladder incontinence in a single institution.

INTRODUCTION: Incontinent pediatric neurogenic bladder (NB) patients face social ostracization and potential renal deterioration. Reconstructive surgery, after maximal medical therapy, requires a difficult decision-making process. Current literature for NB surgeries is difficult to interpret given definitions of dryness, use of augmentation cystoplasty (AC) and the lack of renal preservation. This study assesses the results of a defined surgical protocol to treat incontinent NB patients, using a new composite outcome measure, which includes upper tracts status and a definition of dryness. MATERIALS AND METHODS: This is a retrospective cohort study assessing 33 consecutive incontinent NB patients (Spina bifida 31, Sacral agenesis- 2) who underwent one of 2 procedures between 2008 and 2021. AC with a Mitrofanoff procedure (MP) was performed in patients who had a high detrusor leak point pressure (DLPP) and significant bladder trabeculations (N = 21, Group 1). Children with a low DLPP and non-trabeculated bladders, underwent a modified Young-Dees-Leadbetter/Mitchell procedure with a 360° autologous rectus fascial sling (BOP) with concomitant AC and MP (N-12, Group 2). Post-operative success was defined using a composite grading of success assessing dryness, upper tract stability and medication use. RESULTS: The mean age at surgery was 11.6 years (SD = 6 years), with 21 in Group 1 and 12 in Group 2. Mean follow-up was 3.25 years, with a minimum 24-month follow-up period. Success rate was 90% in Group 1 and 66% in Group 2. No patient had upper tract deterioration following surgery. Redo-surgical intervention, was required in 38% of Group 1 and 50% of Group 2 patients. These include 3 bladder neck injections in Group 1 and 2 bladder neck closure in Group 2, with a final success rate to 95 % in Group 1 and 83 % in Group 2. DISCUSSION: Achieving dryness and preserving upper tracts is a challenge in incontinent NB patients. Dryness rates achieved in this study is comparable, given complications and redo-surgery. Primary bladder neck closure is a radical intervention, but Group 2 patients, may benefit from an upfront discussion of the pros and cons of a bladder neck closure primarily or as a secondary procedure. CONCLUSIONS: Isolated AC obtains acceptable results for a selected subset of incontinent NB patients with significant bladder trabeculation. For those requiring a BOP, the success rate is relatively lower with the higher rate of potential complications and need for redo-surgery.

The management and outcomes of hepatocellular carcinoma in sub-Saharan Africa: a systematic review.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of mortality in sub-Saharan Africa (SSA). This systematic review aimed to appraise all population-based studies describing the management and outcomes of HCC in SSA. METHODS: A systematic review based on a search in PubMed, PubMed Central, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), AfricaWide and Cochrane up to June 2023 was performed. PRISMA guidelines for systematic reviews were followed. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration no: CRD42022363955). RESULTS: Thirty-nine publications from 15 of 48 SSA countries were identified; 3989 patients were studied. The majority (74%) were male, with median ages ranging from 28 to 54 years. Chronic Hepatitis B infection was a leading aetiology and non-cirrhotic HCC was frequently reported. Curative treatment (liver resection, transplantation and ablation) was offered to 6% of the cohort. Most patients (84%) received only best supportive care (BSC), with few survivors at one year. CONCLUSION: The majority of SSA countries do not have data reporting outcomes for HCC. Most patients receive only BSC, and curative treatment is seldom available in the region. Outcomes are poor compared to high-income countries.

Trimeric Tobramycin/Nebramine Synergizes ß-Lactam Antibiotics against Pseudomonas aeruginosa.

ß-Lactam antibiotics remain one of the most effective therapeutics to treat infections caused by Gram-negative bacteria (GNB). However, since ancient times, bacteria have developed multiple resistance mechanisms toward this class of antibiotics including overexpression of ß-lactamases, suppression of porins, outer membrane impermeability, overexpression of efflux pumps, and target modifications. To cope with these challenges and to extend the lifetime of existing ß-lactam antibiotics, ß-lactamase inhibitors are combined with ß-lactam antibiotics to prevent antibiotic inactivation by ß-lactamases. The combination therapy of an outer membrane permeabilizer with ß-lactam antibiotics is an alternative approach to overcoming bacterial resistance of ß-lactams in GNB. This approach is of particular interest for pathogens with highly impermeable outer membranes like Pseudomonas aeruginosa. Previous studies have shown that outer membrane permeabilizers can be designed by linking tobramycin and nebramine units together in the form of dimers or chimeras. In this study, we developed trimeric tobramycin and nebramine-based outer membrane permeabilizers presented on a central 1,3,5-triazine framework. The resultant trimers are capable of potentiating outer membrane-impermeable antibiotics but also ß-lactams and ß-lactam/ß-lactamase inhibitor combinations against resistant P. aeruginosa isolates. Furthermore, the microbiological susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached by a triple combination consisting of an outer-membrane permeabilizer/ß-lactam/ß-lactamase inhibitor in ß-lactam-resistant P. aeruginosa isolates. Overall, our results indicate that trimeric tobramycins/nebramines can rescue clinically approved ß-lactams and ß-lactam/ß-lactamase inhibitor combinations from resistance.

Exploring Antibiotic-Potentiating Effects of Tobramycin-Deferiprone Conjugates in Pseudomonas aeruginosa.

Metal ions, including Fe3+, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including Pseudomonas aeruginosa. To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of P. aeruginosa. While all TOB-DEF conjugates were inactive against P. aeruginosa, the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, 1c containing a C12 tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant P. aeruginosa isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe3+ concentration.

Effectiveness of pediatric Crawford tube implants when endoscopically assisted by ENT surgeons.

OBJECTIVE: Epiphora in pediatrics is commonly treated with silicone nasolacrimal stents. The most common treatment duration is 3 months, but tubes are often unintentionally removed earlier and are still effective. There is no consensus on how long tubes need to be in situ and what factors influence treatment success. METHODS: A retrospective chart review of patients who underwent Crawford tube placement over a 10-year period (2009-2019) was conducted. Patients were age <18 years and had Crawford tubes placed in conjunction with an otolaryngologist, who performed nasal endoscopy for direct visualization when retrieving Crawford tubes and infracture of the inferior turbinate. Bicanalicular intubation was attempted in all cases; if not possible, monocanalicular intubation was performed. RESULTS: Forty-two patients were included in this study, representing 50 eyes. Spontaneous extrusion of tubes occurred in 54% of eyes. Tubes remained in situ for an average of 17.1 weeks (0-113 weeks). Symptoms resolved in 86% of patients, similar to procedures without endoscopy. There were no intraoperative complications. There was no association between the rate of persistent symptoms and duration of treatment. CONCLUSION: Nasolacrimal duct intubation using Crawford tubes performed under direct endoscopic visualization is consistently successful for the treatment of epiphora. Although epiphora can be self-resolving, persistent symptoms typically lasting past the first year of birth, warrant treatment. Children who receive Crawford tubes for epiphora commonly have spontaneous tube extrusion before treatment duration is complete. However, treatment success was not related to the length of time the tubes were in situ. Endoscopic visualization can help prevent intraoperative complications.

In silico Study and Solvent-free one-pot Synthesis of Tetrahydropyrimidine derivatives by Mechanochemistry Approach for Targeting Human Neutrophil Elastase against Lung Cancer.

BACKGROUND: Pyrimidine derivative has evinced its biological importance in targeting lung cancer by inhibiting neutrophil elastase. METHODS: All THPM derivatives were synthesized by the grindstone method at ambient temperature followed by molecular docking study for efficient binding interaction of THPM compounds by targeting human neutrophil elastase (HNE) (PDB ID: 5A0A) and In-silico ADMET study using PkCSM. Moreover, all synthesized compounds were characterized by spectroscopy techniques and screened for anti-cancer activity using in vitro HNE assay kit. RESULTS: We reported a one-pot solvent-free mechanochemical approach for synthesizing tetrahydropyrimidine (THPM) derivatives from various aromatic aldehydes, ethyl cyanoacetate, and urea followed by in silico study and evaluation against human neutrophil elastase (HNE) for treatment of lung cancer. We calibrated the best molecules that bound to specific targets more efficiently using a molecular docking approach and provided the desired efficacy. In-silico ADMET studies revealed that all best-scored compounds had drug-like characteristics for potential use as human neutrophil elastase inhibitors (HNE) in lung cancer treatment. Additionally, the in vitro studies revealed that compounds 1, 2, and 8 show potent HNE inhibitory activity for lung cancer treatment. CONCLUSION: In a nutshell, the tetrahydropyrimidine (THPM) scaffold and its derivatives may serve as potential HNE inhibitors for the development of a promising anti-cancer agent.

Anticholinergic treatment for sialorrhea in children: A systematic review.

Background: Sialorrhea in children can be associated with adverse physical and social effects. Treatment using anticholinergic medications has been shown to offer symptomatic relief, but there is no consensus regarding which treatment is the most efficacious. Objective: To examine the effectiveness of anticholinergic medications for sialorrhea in children. Methods: A systematic review was carried out in Medline, EMBASE, Cochrane, Scopus, and the Web of Science from inception until April 29, 2020. Studies reporting original data on the efficacy of anticholinergic medications in the management of sialorrhea in children aged 0 to 17 years of age were included. This review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. Data on study design, setting, population, pharmacologic intervention(s), comparator(s), outcomes, and results were extracted and summarized. Results: The search strategy identified 2,800 studies of which 27 articles were included in the synthesis, including five randomized controlled trials. Each anticholinergic undergoing experimental study (glycopyrrolate, scopolamine/hyoscine, trihexyphenidyl/benzhexol, benztropine, and atropine) showed evidence of efficacy. Adverse side effects were common. Significant heterogeneity exists in the studies' methodology and the variability of outcome measures used between studies precluded a meta-analysis. Conclusions: Glycopyrrolate, scopolamine/hyoscine, trihexyphenidyl/benzhexol, benztropine, and atropine have all shown efficacy in the treatment of sialorrhea in children. The small number of reports and the variability in study design precluded a meta-analysis. More studies are needed with uniformity in outcome measures to help guide evidence-based decision making. A guidance table is presented.

Role of Natural and Synthetic Flavonoids as Potential Aromatase Inhibitors in Breast Cancer: Structure-Activity Relationship Perspective.

World Health Organization categorized breast cancer as one of the leading cancer types in females worldwide, and its treatment remains challenging. Accumulated evidence suggested the role of estrogen and its metabolites in pre- and post-menopausal women. Upregulation of estrogen-dependent aromatase is significantly involved in the pathogenesis of breast cancer. Several aromatase inhibitors, such as exemestane, formestane, and letrozole, are being used clinically, owing to their estrogen suppression role. Apart from these drugs, several other molecules, such as natural and synthetic flavonoids, have been reported widely for a similar biological activity. However, some reasonable modifications are required for these structures to achieve desired efficacy and to alleviate toxicity. Designing a novel aromatase inhibitor will be possible if we can establish a rational correlation between the chemistry and biological features of the existing molecules. The benzopyranone- ring system, present in the flavonoid molecules, has been reported as a pharmacophore due to its inhibitory activity on aromatase, which helps repress breast cancer progression. This essential feature has been utilized to modify several natural flavonoids into 5 and 7 hydroxy/methoxy flavone, 4-imidazolyl/triazolyl flavone, 5,4'- diamino flavone, 7,8- benzo-4-imidazolyl flavone, α-naphthoflavone, and 2-azole/thiazolyl isoflavone derivatives. These scaffolds have been considered in this review for meticulous study in aspects of the structure-activity relationship for aromatase inhibitory activity, and it would likely pave the way for designing a potential lead candidate in the future.

Cervicofacial Actinomycosis in the Pediatric Population: Presentation and Management.

BACKGROUND: Infection caused by Actinomyces species is a rare cause of head and neck infection in children. This chronic cervicofacial infection can present with localized swelling, abscess formation, sinus drainage and can be complicated by osteomyelitis. METHODS: Presented are 2 pediatric cases of secondary actinomycosis in the context of congenital lesions: 1 patient with a previously excised preauricular sinus and another with a persistent sublingual mass. A comprehensive literature search was conducted for reported cases of pediatric actinomycosis in the cervicofacial region. RESULTS: Both cases presented were successfully treated with a combination of complete surgical excision of the lesions and prolonged antibiotic therapy. Thirty-four pediatric cases of cervicofacial actinomycosis are reviewed, 2 presented herein, and 32 from the published literature. There was equal gender distribution and the median age was 7.5 years. The most common site for infection was the submandibular area. Four (12%) of cases arose in pre-existing congenital lesions. Most patients were treated with penicillin-based antibiotics for a median duration of 6 months following surgical excision or debridement. CONCLUSIONS: Actinomycosis is a rare infection of the cervicofacial region; secondary infections arising from congenital lesions of the head and neck are even more rare. A previously excised pre-auricular sinus and a sublingual dermoid cyst are not previously reported sites of infection. Actinomycosis should be suspected in chronically draining sinuses of the head and neck region and confirmed through anaerobic culture. Osteomyelitis is a potential complication and magnetic resonance (MR) imaging is warranted. Long-term antibiotic therapy with a penicillin-based antibiotic and surgical excision should be considered.

Disruption of desmosome function leads to increased centrosome clustering in 14-3-3γ-knockout cells with supernumerary centrosomes.

14-3-3 proteins are conserved, dimeric, acidic proteins that regulate multiple cellular pathways. Loss of either 14-3-3ε or 14-3-3γ leads to centrosome amplification. However, we find that while the knockout of 14-3-3ε leads to multipolar mitoses, the knockout of 14-3-3γ results in centrosome clustering and pseudo-bipolar mitoses. 14-3-3γ knockouts demonstrate compromised desmosome function and a decrease in keratin levels, leading to decreased cell stiffness and an increase in centrosome clustering. Restoration of desmosome function increased multipolar mitoses, whereas knockdown of either plakoglobin or keratin 5 led to decreased cell stiffness and increased pseudo-bipolar mitoses. These results suggest that the ability of the desmosome to anchor keratin filaments maintains cell stiffness, thus inhibiting centrosome clustering, and that phenotypes observed upon 14-3-3 loss reflect the dysregulation of multiple pathways.

Collocating Novel Targets for Tuberculosis (TB) Drug Discovery.

BACKGROUND: Mycobacterium tuberculosis, being a resistive species is an incessant threat to the world population for the treatment of Tuberculosis (TB). An advanced genetic or a molecular level approach is mandatory for both diagnosis and therapy as the prevalence of multi drug-resistant (MDR) and extensively drug- resistant (XDR) TB. METHODS: A literature review was conducted, focusing essentially on the development of biomarkers and targets to extrapolate the Tuberculosis Drug Discovery process. RESULTS AND DISCUSSION: In this article, we have discussed several substantial targets and genetic mutations occurring in a diseased or treatment condition of TB patients. It includes expressions in Bhlhe40, natural resistance associated macrophage protein 1 (NRAMP1) and vitamin D receptor (VDR) with its mechanistic actions that have made a significant impact on TB. Moreover, recently identified compounds; imidazopyridine amine derivative (Q203), biphenyl amide derivative (DG70), azetidine, thioquinazole, tetrahydroindazole and 2- mercapto- quinazoline scaffolds for several targets such as adenosine triphosphate (ATP), amino acid and fatty acid have been briefed for their confirmed hits and therapeutic activity.

Altered mitochondrial fusion drives defensive glutathione synthesis in cells able to switch to glycolytic ATP production.

Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or are linked to numerous neurodegenerative, neuromuscular, and metabolic diseases. It is generally thought that cells with altered mitochondrial structure are prone to mitochondrial dysfunction, increased reactive oxygen species generation and widespread oxidative damage. The objective of the current study was to investigate the relationship between mitochondrial dynamics and the master cellular antioxidant, glutathione (GSH). We reveal that mouse embryonic fibroblasts (MEFs) lacking the mitochondrial fusion machinery display elevated levels of GSH, which limits oxidative damage. Moreover, targeted metabolomics and 13C isotopic labeling experiments demonstrate that cells lacking the inner membrane fusion GTPase OPA1 undergo widespread metabolic remodeling altering the balance of citric acid cycle intermediates and ultimately favoring GSH synthesis. Interestingly, the GSH precursor and antioxidant n-acetylcysteine did not increase GSH levels in OPA1 KO cells, suggesting that cysteine is not limiting for GSH production in this context. Post-mitotic neurons were unable to increase GSH production in the absence of OPA1. Finally, the ability to use glycolysis for ATP production was a requirement for GSH accumulation following OPA1 deletion. Thus, our results demonstrate a novel role for mitochondrial fusion in the regulation of GSH synthesis, and suggest that cysteine availability is not limiting for GSH synthesis in conditions of mitochondrial fragmentation. These findings provide a possible explanation for the heightened sensitivity of certain cell types to alterations in mitochondrial dynamics.

Defining the advantages and exposing the limitations of endoscopic variceal ligation in controlling acute bleeding and achieving complete variceal eradication.

BACKGROUND: Bleeding esophageal varices (BEV) is a potentially life-threatening complication in patients with portal hypertension with mortality rates as high as 25% within six weeks of the index variceal bleed. After control of the initial bleeding episode patients should enter a long-term surveillance program with endoscopic intervention combined with non-selective ß-blockers to prevent further bleeding and eradicate EV. AIM: To assess the efficacy of endoscopic variceal ligation (EVL) in controlling acute variceal bleeding, preventing variceal recurrence and rebleeding and achieving complete eradication of esophageal varices (EV) in patients who present with BEV. METHODS: A prospectively documented single-center database was used to retrospectively identify all patients with BEV who were treated with EVL between 2000 and 2018. Control of acute bleeding, variceal recurrence, rebleeding, eradication and survival were analyzed using Baveno assessment criteria. RESULTS: One hundred and forty patients (100 men, 40 women; mean age 50 years; range, 21-84 years; Child-Pugh grade A = 32; B = 48; C = 60) underwent 160 emergency and 298 elective EVL interventions during a total of 928 endoscopy sessions. One hundred and fourteen (81%) of the 140 patients had variceal bleeding that was effectively controlled during the index banding procedure and never bled again from EV, while 26 (19%) patients had complicated and refractory variceal bleeding. EVL controlled the acute sentinel variceal bleed during the first endoscopic intervention in 134 of 140 patients (95.7%). Six patients required balloon tamponade for control and 4 other patients rebled in hospital. Overall 5-d endoscopic failure to control variceal bleeding was 7.1% (n = 10) and four patients required a salvage transjugular intrahepatic portosystemic shunt. Index admission mortality was 14.2% (n = 20). EV were completely eradicated in 50 of 111 patients (45%) who survived > 3 mo of whom 31 recurred and 3 rebled. Sixteen (13.3%) of 120 surviving patients subsequently had 21 EV rebleeding episodes and 10 patients bled from other sources after discharge from hospital. Overall rebleeding from all sources after 2 years was 21.7% (n = 26). Sixty-nine (49.3%) of the 140 patients died, mainly due to liver failure (n = 46) during follow-up. Cumulative survival for the 140 patients was 71.4% at 1 year, 65% at 3 years, 60% at 5 years and 52.1% at 10 years. CONCLUSION: EVL was highly effective in controlling the sentinel variceal bleed with an overall 5-day failure to control bleeding of 7.1%. Although repeated EVL achieved complete variceal eradication in less than half of patients with BEV, of whom 62% recurred, there was a significant reduction in subsequent rebleeding.

Percutaneous Cholecystostomy Placement in Cases of Non-operative Cholecystitis: A Retrospective Cohort Analysis.

BACKGROUND: Acute (calculous) cholecystitis (AC) is an extremely common surgical presentation, managed by cholecystectomy. Percutaneous cholecystostomy (PC) is an alternative; however, its safety and efficacy, along with subsequent cholecystectomy, are underreported in South Africa, where patients often present late and access to emergency operating theatre is constrained. The aim of the study was to demonstrate the outcomes of PC in patients with AC not responding to antimicrobials. MATERIALS AND METHODS: A retrospective cohort review of patient records, who underwent PC in Groote Schuur Hospital, Cape Town, between May 2013 and July 2016, was performed. Patients with PC for malignancy or acalculous cholecystitis were excluded. Technical success, clinical response, procedure-related morbidity and mortality were recorded. Interval LC parameters were investigated. RESULTS: Technical success and clinical improvement was seen in 29 of 37 patients (78.38%) who had PC. Malposition (8.11%) was the most common complication. Two patients required emergency surgery (5.4%), while one tube was dislodged. Median tube placement duration was 25 days (range 1-211). Post-procedure, 16 patients (43.24%) went on to have LC, of which 50% (eight patients) required conversion to open surgery and 25% (four) had subtotal cholecystectomy. Median surgical time was 130 min. There were no procedure-related mortalities but eight patients (21.62%) died in the 90-day period following tube insertion. CONCLUSION: In patients with AC, PC is safe, with high technical success and low complication rate. Subsequent cholecystectomy should be performed, but is usually challenging. The requirement for PC may predict a more complex disease process.

Drug Stereochemistry: A Prodigy For Pharmacology and Drug Development.

Stereochemistry has evinced the importance of many chiral drugs with respect to drug designing and development. A literature review was conducted for several chiral drugs involving pharmacokinetic and pharmacodynamic parameters of their enantiomers along with their uses in certain diseased conditions. This article mainly includes the pharmacological profile review of some chiral drugs and the aspects due to which the single enantiomer is of importance as compared to the racemic mixture of the drug. This was achieved by moderating the side effects or toxic effects; or by the potentiated activity of the single enantiomer. Resolution deals with the separation of racemic compounds which shows up the credibility to obtain the desired enantiomeric properties. As isomers vary in their pharmacokinetic and pharmacodynamic profiles, chiral drugs have showcased considerable importance in the drug development process. Both the enantiomers have a different pharmacological profile in the treatment of a disease, which differentiates them from drug racemates.